Cervical cancer is the second most common type of cancer in women worldwide, with about 500,000 new cases of cervical cancer and about 250,000 cervical cancer-related deaths reported each year. Cervical cancer develops in the epithelium layer of the cervix, and usually begins slowly with precancerous abnormalities, or cervical dysplasia. The most common (75%) cervical cancer, called squamous cell carcinoma, arises from changes in the squamous cells of the epithelium. Another 20% of the cervical cancers, called endocervical adenocarcinomas, arise from changes in cervical glandular cells. In rare cases, cancer can occur in the stroma, cells that form the supportive tissue around the cervix.
Cervical intraepithelial neoplasia (CIN) is characterized by squamous cells of the epithelium becoming abnormal in size and shape and beginning to multiply. CIN may become cancerous. Progression of CIN to cancer is characterized by the ability of the cells to actually invade into surrounding tissues. To help determine the risk of progressing into cancer, CIN is further categorized into three levels of severity. CIN I refers to mild abnormalities that rarely (1%) develop into cervical cancer. This condition may progress if untreated but is often self-limiting, usually returning to normal without treatment. CIN II refers to the lesions that often appear more aggressive under the microscope and may progress to cancer unless treated. In women with untreated CIN II, the risk for progression is 16% by two years and 25% after five years. CIN III refers to the most aggressive form of CIN, and carries the highest chance of progressing to invasive cancer if not removed. CIN III includes Carcinoma In Situ (CIS). CIS is characterized by cells that look cancerous under the microscope but have not yet invaded the surrounding tissue. Most untreated CIS will develop into invasive cancers over a period of 10 to 12 years.
Human papillomavirus (HPV) has been detected in virtually all invasive cervical cancers. It is spread mainly by sex with an infected partner and is now considered to be the primary risk factor for this disease. More than 30 genetic variants of HPV can be passed through sexual contact from one person to another. However, only high-risk HPV (HR-HPV) types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, and 69) are associated with moderate dysplasia (CIN II) and carcinoma in situ (CIN III). HPV type 18 and HPV type 16 are particularly dangerous.
When a cervical abnormality is detected and treated in precancerous stages, cervical cancer is preventable. A cytological staining of simple cervical smears was developed by Dr. George Papanicolaou in the 1930's and named after him as the Pap Smear. In the Pap Smear method, live cells are collected by gently scraping the surface of the cervix with a sampling device, such as a plastic spatula or a cytobrush. Cells from the spatula or cytobrush are directly smeared on a slide and then fixed and stained using the Papanicolaou stain. Physicians transfer the slides to a pathology lab for microscopic viewing.
Specimens are reviewed by cytotechnologists and cytopathologists under microscope. Malignant cells can be detected based on their morphological differences from the normal cells. A system called the Bethesda system is used to categorize the malignant cells into four malignancy levels: 1) atypical squamous cells of undetermined significance (ASCUS), which are mildly abnormal cells on the surface of the cervix; 2) low-grade squamous intraepithelial lesions (LSIL), which could associate with CIN I, CIN II; or CIN III on biopsy; 3) high-grade squamous intraepithelial lesions (HSIL), which are associated with moderate and severe dysplasia and associated with CIN II or CIN III on biopsy; and 4) squamous cell carcinoma (SCC). Cells at different levels differ in cell morphology, and their nucleus to cytoplasm ratio increases as the malignance level increases.
Liquid-based cytology (LBC) is an improvement over the conventional Pap smear. In LBC the sampling device is first rinsed in a liquid preservative solution to thin the mucous and eliminate debris that can obscure the cells. The cells are then mechanically dispersed into a liquid medium. A representative aliquot of samples is transferred to a slide to form a clear, thin monolayer using an automatic machine such as the ThinPrep (Cytyc Corp., Boxborough, Mass.). The slides are then examined the same way as described above.
The Pap smear and LBC methods are based on subjective visual readings of cell morphologies. The sensitivity of the test is relatively low, which results in a high false-negative rate. In addition, these tests require highly trained staff and adequate laboratories, which make the tests labor-intensive and expensive.
Various methods for detecting cervical abnormalities (such as cervical dysplasia) are described in WO04/038418, US2002006685, and US20040002125. There is a need for more accurate, affordable, and automated methods and devices for cervical cancer screening.
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